Hepatic Lipin 1β Expression Is Diminished in Insulin-Resistant Obese Subjects and Is Reactivated by Marked Weight Loss

Abstract

OBJECTIVE— Lipin 1 plays critical roles in controlling energy metabolism. We sought to determine the expression of lipin 1 isoforms (lipin 1α and -β) in liver and adipose tissue of obese subjects and to evaluate cellular mechanisms involved in the regulation of lipin 1 expression by physiologic stimuli. RESEARCH DESIGN AND METHODS— The expression of lipin 1α and -β was quantified in liver and adipose tissue of extremely obese (average BMI 60.8 kg/m2) human subjects undergoing gastric bypass surgery (GBS). Second, the expression of lipin 1 was evaluated in HepG2 cells in response to overexpression of peroxisome proliferator–activated receptor-γ coactivator (PGC)-1α under normal or hyperinsulinemic conditions. RESULTS— The expression of lipin 1β in liver and adipose tissue was inversely related to BMI, fasting plasma insulin concentration, and the homeostasis model assessment of insulin resistance but was significantly increased by marked weight loss and insulin sensitization following GBS. Hepatic lipin 1β mRNA levels were strongly correlated with the expression of PGC-1α, and overexpression of PGC-1α in HepG2 cells increased lipin 1 expression. Conversely, hyperinsulinemic culture conditions downregulated the expression of lipin 1β, PGC-1α, and their known target genes involved in mitochondrial metabolism in HepG2 cells. Finally, overexpression of lipin 1β or PGC-1α reversed the effect of hyperinsulinemia on the expression of their target genes. CONCLUSIONS— These studies suggest that hepatic lipin 1β and PGC-1α expression are downregulated by obesity and obesity-related metabolic perturbations in human subjects, likely due to alterations in insulin concentration or sensitivity.